Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity.

BACKGROUND: Gastrointestinal hormone release and the regulation of appetite and body weight are thought to be dysbalanced in obesity. However, human data investigating the expression of gastrointestinal hormones in the obese are rare. We studied the expression of ghrelin, leptin, and the serotonergic system in stomach tissue and serum of obese and non-obese individuals. METHODS: Gastric tissue and serum were collected from 29 adult obese (BMI 48.7 ± 10.6 kg/m(2) ; mean ± SD) who underwent laparoscopic sleeve gastrectomy. Gastric biopsies, surgery specimen or serum was obtained from 35 adult non-obese humans (BMI 22.7 ± 1.9 kg/m(2) ). Ghrelin, ghrelin O-acyl transferase (GOAT), leptin, leptin receptor, and tryptophan hydroxylase 1 (TPH1) mRNA expression were measured by qRT-PCR. Serotonin (5HT) and leptin protein concentration were quantified in tissue extracts and serum; GOAT and ghrelin-positive cells were immunohistologically quantified in tissue. Additionally, 21 blood immune markers were analyzed. KEY RESULTS: In gastric tissue, GOAT-positive cells were reduced (p < 0.01), but ghrelin-positive cells and mRNA were increased (both p < 0.05) in obese compared with non-obese individuals. Gastric leptin (p < 0.001) and leptin receptor (p < 0.001) mRNA expression, as well as leptin concentrations in serum (p < 0.001), were increased in obese compared with non-obese individuals. Serum 5HT was reduced (p < 0.05), while tissue 5HT and TPH1 mRNA were reduced only by trend. Interleukin 1 receptor a (IL1Ra), IL-8, IL-12, and monocyte chemoattractant protein 1 (IL1Ra) were increased and IL1Ra correlated negatively with serum leptin. CONCLUSIONS & INFERENCES: Our data indicate that obesity causes a dysregulation of gastrointestinal hormones at the tissue level and serum, including a negative correlation with an increased marker of subclinical inflammation.

Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter.

BACKGROUND: Enterochromaffin cells and enteric neurons synthesize and release serotonin (5-HT). Reuptake, mediated by a plasmalemmal transporter (SERT) terminates the action of released 5-HT. Serotonin secretion and serotonin reuptake transporter (SERT) expression have been reported to be decreased in TNBS-induced experimental colitis and in patients with ulcerative colitis. The present study was designed to utilize the transgenic deletion of SERT as a gain-of-function model to test the hypothesis that 5-HT is a pro-inflammatory mediator in experimental colitis. METHODS: Colitis was compared in animals with IL10(+/+)SERT(+/+) (wild-type), IL10(-/-)SERT(+/+), IL10(-/-)SERT(+/-), and IL10(-/-)/SERT(-/-) (double knockout) genotypes. Macroscopic and histological damage scores were evaluated after a time period of up to 15 weeks. KEY RESULTS: Serotonin reuptake transporter expression was significantly increased in the inflamed colons of IL-10(-/-) mice, which displayed intestinal damage and a minor decrement in general health. General health was significantly worse and intestinal inflammation was more severe in IL-10(-/-)SERT(+/-), and IL-10(-/-)SERT(-/-) mice than in IL-10(-/-)SERT(+/+) or wild-type animals. Regardless of the associated SERT genotype, the number of 5-HT-immunoreactive cells was decreased by approximately 55-65% in all mice lacking IL-10. CONCLUSIONS & INFERENCES: Our observations indicate that colitis associated with IL-10 deficient mice is enhanced when the IL-10 deficiency is combined with a SERT deficiency. The data support the concept that 5-HT is a pro-inflammatory mediator in the gut.